This collaborative proposal combines recent advances in the areas of red blood cell encapsulation, noninvasive optical monitoring and chemical synthesis of optical probes to develop a new technique that allows long term noninvasive monitoring of key blood parameters. To enable this novel methodology, this is the first attempt to encapsulate optical sensing elements in red blood cells (RBCs) to monitor plasma parameters. Combining the biomedical optics knowledge of the Meissner group, the RBC physiology knowledge of the Milanick group and the chemical synthesis abilities of the Glass group will result in the demonstration of a revolutionary noninvasive optical monitoring technique that can be broadly applied to long term continuous monitoring. Encapsulating optical sensing dyes inside RBCs and then returning the cells to the animal or person will for the first time enable continuous noninvasive optical monitoring for months in vivo. Leveraging expertise in biomedical engineering, chemistry and life sciences, the objectives of our collaboration are first to develop novel NIR fluorescent sensors and load them into RBCs using its reversible lysis pore, second to develop optical instrumentation for sensor interrogation with an integrated theory/experiment approach, third to test the loaded RBC's and the developed instrumentation in a rat model. The project will result in the development and proof-of-concept of a revolutionary biomedical sensing technique that employs functionalized RBCs for long term monitoring of blood analytes. A noninvasive monitoring system for blood parameters would have high impact on disease/physiological tracking for chronic conditions such as diabetes. Unlike conventional techniques, the innovative proposed sensing system utilizes cells from the body, RBCs that live for 120 days, to prevent immune system responses. With optical probes inside RBCs, circulating RBCs will provide constant sampling of blood analytes and overcome the major impediment to conventional implantable monitors. Significant knowledge and techniques about loading RBCs with optically active sensors will also be developed. By optically coupling the sensors, the technique enables noninvasive interrogation of blood analytes at little or no measurement cost. This facilitates frequent testing for both on-demand and continuous monitoring.